Recently, the adipose tissue has been shown to be an endocrine organ that actively produces and secretes many bioactive substances, called adipocytokines, which play a crucial role in the control of systemic glucose and lipid metabolism (Nature, 414:799-806, 2001). Adiponectin is one of adipocytokines identified as the most abundantly-expressing gene in human adipocytes and as a hormone (Biochemical and Biophysical Research Communication, 221:286-289, 1996). Adiponectin is specifically produced and secreted in adipocytes, and exists abundantly in the blood.
Many research results have shown that adiponectin is an antidiabetic, antiarteriosclerotic, and antiobestic hormone, which is closely associated with the onset and progress of metabolic diseases. For example, plasma adiponectin concentration was decreased in patients with ischemic heart diseases or insulin-resistant diabetes (Circulation, 100:2473-2476, 1999; Arteriosclerosis, Thrombosis, and Vascular Biology, 20:1595-1599, 2000). Furthermore, in patients with mutations in the adiponectin gene, the decrease in plasma adiponectin concentration was associated with the onset of insulin-resistant diabetes or atherosclerosis (Diabetes, 50: 1126-1133, 2002). In obese diabetic monkeys, the progressive reduction in plasma adiponectin was deeply associated with the aggravation of insulin resistance (Diabetes, 50:1126-1133, 2001). In adiponectin-deficient mice, diabetes was caused by the load of high sucrose and high fat diet, and neointimal thickening after artery injury was remarkably accentuated. Adenovirus-mediated supplement of adiponectin into the knockout mice eminently improved the lesion (Nature Medicine, 8:731-737, 2002, Journal of Biological Chemistry, 277:37487-37491, 2002). Moreover, adenoviral supplement of adiponectin into apolipoprotein E-deficient mice suppressed the progress of arteriosclerosis (Circulation, 106:2767-2770, 2002). When recombinant adiponectin protein was administrated in metabolically-impaired mice, the improvement of insulin resistance and hypoglycemic action were seen (Nature Medicine, 7:941-946, 2001, Nature Medicine, 7:947-953, 2001). According to these facts, the therapy raising plasma adiponectin concentration is thought to be effective in improving the condition of patients with hypoadiponectinemia. However, plasma adiponectin concentration in human, which is 5-20 μg/ml (Biochemical and Biophysical Research Communication, 257:79-83, 1999), is extremely high compared with other blood hormones. Considering this respect, in patients with hypoadiponectinemia, it is thought that the substitution therapy of recombination adiponectin protein to normalize plasma concentration would be accompanied by various great difficulties in continuous high-dose administration of the protein or the prevention of in vivo enzymatic hydrolysis of the protein.